Over the past decade, investigators have come to recognize the importance of the extracellular matrix (ECM) in directing the growth, differentiation and function of the overlying epithelium. Getzenberg et al., "The Tissue Matrix: Cell Dynamics and Hormone Action", Endocrine Rev. 1990, 11:399. The interaction between cell and extracellular matrix (or substratum) is mediated by several classes of cell adhesion molecules, one of the most important being the integrins. Albelda et al., "Integrins and Other Cell Adhesion Molecules", FESEB J. 1990, 4:2868. Buck et al., "Integrin, a Transmembrane Glycoprotein Complex Mediating Cell-Substratum Adhesion", J. Cell Sci. Suppl. 1987, 8:231. This diverse family of glycoprotein receptors is expressed on the cell membrane as heterodimeric .alpha. and .beta. integrin subunits and is involved in both cell-cell and cell-substratum adhesion. Specific recognition and binding of extracellular matrix (ECM) components such as fibronectin (FN), laminin (LM) and collagen (Col) transmit information to the cytoskeletal structure, an interaction which may have major roles in promoting hormone responsiveness and genomic activation. Burridge et al., "Focal Adhesions: Transmembrane Junctions Between the Extracellular Matrix and the Cytoskeleton", Ann. Rev. Cell. Biol. 1988, 4:487 and Getzenberg et al. supra.
Although extensive information exists about specific integrin proteins, for example, Hemler, M. E. "VLA Proteins in the Integrin Family: Structures, Functions and Their Role on Leukocytes", Annu. Rev. Immunol. 1990, 8:365, little is known concerning the distribution of these receptors in the female reproductive tract. In the uterus, the endometrium, composed of glandular epithelium and associated mesenchyme (stroma), maintains complex temporal and spatial functions in response to the cyclic hormonal milieu. While Tabibzadeh reported that dynamic alterations in integrin expression accompany the other histologic changes that temporally mark the menstrual cycle, Tabibzadeh, S., "Patterns of Expression of Integrin Molecules in Human Endometrium Throughout the Menstrual Cycle", Hum. Reprod. 1992, 7:876, the search for morphological or biochemical markers for uterine receptivity has been unsuccessful to date as reported by Rogers and Murphy, "Uterine Receptivity for Implantation: Human Studies", in Blastocyst Implantation 1989, Yoshinaga, K. ed., Serono Symposia, p. 231. Once such markers are identified, their role in endometrial phenomena including embryo implantation, fertility, contraception and endometrial maturation and receptivity can likely also be identified. Thus, as some integrins appear to meet the criteria for markers of receptivity there is a great need for methods of detecting integrin cell adhesion molecules in endometrium.
Asynchrony between uterine and embryonic development has been suggested as a cause of pregnancy loss, on the basis of a misalignment between endometrial and embryonic receptivity, see Pope, et al., "Uterine Asynchrony: A cause of Embryonic Loss", Biol. Reprod. 1988, 39:999.
The relationship between minimal endometriosis and nulliparity and infertility remains controversial. While many cogent arguments exist to support this association, many clinicians today still do not believe that minimal or mild forms of the disease are detrimental to a couple's fertility. Several studies comparing women with normal endometrium to women with mild or minimal endometriosis have demonstrated a decrease in cycle fecundity, such as success rates in donor programs, IVF, or GIFT, supported by animal models. One reason for this lack of acceptance is the finding of many studies that expectant management yields pregnancy rates as high as most currently used treatments.
Of the many mechanisms suggested to explain the decline in cycle fecundity of endometriosis patients, a defect in uterine receptivity has received perhaps the least attention. Fedele reported specific changes in the native endometrium in women with severe endometriosis, Fedele, L., et al., "Structural and Ultrastructural Defects in Preovulatory Endometrium of Normo-Ovulating Infertile Women with Minimal or Mild Endometriosis", Fertil. Steril. 1990, 53:989. Yovich suggested that severe endometriosis was associated with a defect in implantation, based on IVF-ET experience, see Yovich et al., "Hormonal Profiles and Embryo Quality in Women with Severe Endometriosis Treated by In Vitro Fertilization and Embryo Transfer", Fertil. Steril. 1988, 50:308. There is data from studies in the rabbit to suggest that implantation is adversely affected by surgically induced endometriosis, and that the effect is mediated by the peritoneal fluid, see Hahn et al., "Experimental Evidence for Failure to Implant as a Mechanism of Infertility Associated with Endometriosis", Am. J. Obstet. Gynecol. 1986, 155:1109.
Endometriosis is a disorder that affects an estimated 2-5% of the general fertile female population, yet its prevalence in infertile women approaches 30-50%, Peterson et al., "Laparoscopy of the infertile Patient", Obstet. Gynecol. 1970, 36:667. While many affected women may have no symptoms, others suffer from dysmenorrhea (painful, difficult menstruation), dyspareunia (pain during intercourse), menstrual disturbances and infertility. That mild or minimal endometriosis is associated with infertility has been suggested by numerous studies, Hasson H. M., "Incidence of Endometriosis in Diagnostic Laparoscopy", J. Reprod. Med. 1976, 16:135 and has been recently reviewed, Bancroft, et al., "Minimal/Mild Endometriosis and Infertility. A Review", Br. J. Obstet. Gynaecol. 1989, 96:454. The mechanism by which minimal endometriosis causes infertility remains uncertain. Adverse effects on folliculogenesis, ovulation, ovum transport, fertilization, sperm quality, embryos, luteal phase function, and an increase in spontaneous abortion rates have all been postulated. These effects may be mediated by elaboration of peritoneal factors such as prostaglandins, cytokines, and growth factors; activation of peritoneal macrophages, or alterations in immune function such as decreased activity of natural killer cells. Kurzrock et al., "LIF: Not Just a Leukemia Inhibitory Factor", Endo. Rev. 1990, 12:208. A few authors have suggested that uterine receptivity to the embryo might be primarily affected by the presence of endometriosis, Muscato, et al., "Sperm Phagocytosis by Human Peritoneal Macrophages: A Possible Cause of Infertility in Endometriosis", Am. J. Obstet. Gynecol. 1982, 144:503 and Yovich et al., supra; and limited data from surgically induced endometriosis in animal models support this hypothesis, Hahn, et al., supra. Further, structural abnormalities have been described in the endometrium of women with endometriosis compared to normal fertile controls, Fedels, et al., supra.
Numerous approaches have been investigated to identify women with endometriosis using non-surgical means. Serum markers such as OC-125, (Barbieri, et al. "Evaluation of a Serological Test for the Diagnosis of Endometriosis using a Monoclonal Antibody OC-125", SGI Annual Meeting 1985; March:331P (abstract)) is increased in women with endometriosis, though the overlap with normal or other disease states severely limits its utility as a diagnostic test, Hornstein, et al., "Menstrual Cyclicity of CA-125 in Patients with Endometriosis", Fertil. Steril. 1992, 58:279 Further, given its graduated elevations with severity of disease, OC-125 has little utility in cases of minimal or mild endometriosis. Other modalities such as MRI or ultrasound also have their highest sensitivity in the presence of advanced endometriosis. To date, no method other than laparoscopy has been demonstrated to provide proven efficacy for the diagnosis of minimal or mild stages of endometriosis.
While uterine receptivity remains a poorly understood phenomenon, the initial attachment of embryo to maternal uterine lining is thought to be a critical step in the implantation process. A window of implantation has been defined by descriptive studies from the 1950s as well more recent studies using advanced reproductive technologies, Hertig et al., 1956 and Navot et al., 1992. The presence of an integrin cell adhesion molecule that reliably appears on the endometrial epithelial cells after day 19 of the normal menstrual cycle, corresponds to this putative time of implantation, Lessey, et al., "Integrin Adhesion Molecules in the Human Endometrium", J. Clin. Invest. 1992, 90:188. The expression of this integrin, the .alpha..sub.v .beta..sub.3 vitronectin receptor, is delayed in women with maturational delay of the endometrium, (where endometrial histology is delayed or retarded because of inadequate hormone levels or decreased response to existing levels of hormones) as well. As it has been suggested by some that infertility due to endometriosis may reflect a defect in uterine receptivity, it is of interest to investigate the expression of this protein in the endometria of women with infertility. The use of integrins as diagnostic tools to investigate uterine receptivity proves to be of significant value in identifying affected individuals and assist in understanding the etiology of infertility associated with mild forms endometriosis.